Genetic Variant NRG1:p.Ala127Pro (chr8-32648096-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000520502.7(NRG1):c.379G>C(p.Ala127Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00925 in 1,614,026 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0077 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0094 ( 90 hom. )

Consequence

NRG1
ENST00000520502.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.35

Publications

12 publications found

Variant links:

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

NRG1 Gene-Disease associations (from GenCC):

schizophrenia 6
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

NRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026865602).

BP6

Variant 8-32648096-G-C is Benign according to our data. Variant chr8-32648096-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2658528.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0094 (13746/1461884) while in subpopulation MID AF = 0.0284 (164/5768). AF 95% confidence interval is 0.0249. There are 90 homozygotes in GnomAdExome4. There are 6658 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000520502.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRG1	NM_013964.5	MANE Select	c.502+31211G>C		intron	N/A	NP_039258.1
NRG1	NM_001322205.2		c.379G>C	p.Ala127Pro	missense	Exon 1 of 9	NP_001309134.1
NRG1	NM_001322206.2		c.379G>C	p.Ala127Pro	missense	Exon 1 of 10	NP_001309135.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRG1	ENST00000520502.7	TSL:1	c.379G>C	p.Ala127Pro	missense	Exon 1 of 3	ENSP00000433289.1
NRG1	ENST00000405005.8	TSL:1 MANE Select	c.502+31211G>C		intron	N/A	ENSP00000384620.2
NRG1	ENST00000287842.7	TSL:1	c.502+31211G>C		intron	N/A	ENSP00000287842.4

Frequencies

GnomAD3 genomes

AF:

0.00776

AC:

1180

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00819

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0207

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00956

Gnomad OTH

AF:

0.00528

GnomAD2 exomes

AF:

0.00920

AC:

2314

AN:

251476

AF XY:

0.00934

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00679

Gnomad ASJ exome

AF:

0.0195

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0229

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.00940

AC:

13746

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00916

AC XY:

6658

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

33480

American (AMR)

AF:

0.00655

AC:

293

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

492

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00172

AC:

148

AN:

86258

European-Finnish (FIN)

AF:

0.0217

AC:

1161

AN:

53414

Middle Eastern (MID)

AF:

0.0284

AC:

164

AN:

5768

European-Non Finnish (NFE)

AF:

0.00973

AC:

10815

AN:

1112008

Other (OTH)

AF:

0.00985

AC:

595

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

874

1748

2621

3495

4369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

412

824

1236

1648

2060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00774

AC:

1178

AN:

152142

Hom.:

Cov.:

AF XY:

0.00807

AC XY:

600

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

41510

American (AMR)

AF:

0.00818

AC:

125

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00166

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0207

AC:

219

AN:

10590

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00956

AC:

650

AN:

67996

Other (OTH)

AF:

0.00523

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00876

Hom.:

Bravo

AF:

0.00655

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00930

AC:

ExAC

AF:

0.00891

AC:

1082

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00981

EpiControl

AF:

0.0108

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NRG1: BP4, BS2

NRG1-related disorder

Benign:1

Feb 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.6

(source)

DANN

Benign

0.29

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

PhyloP100

1.3

PROVEAN

Benign

2.0

REVEL

Benign

0.053

Sift

Benign

1.0

Sift4G

Benign

0.47

Polyphen

0.0

Vest4

0.11

MVP

0.068

ClinPred

0.0046

GERP RS

4.3

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over